By Astrid Sevelsted
Chariman: Zorana Jovanovic Andersen
Opponent: Kirsten Kyvik Ohm
Opponent: Marie Standl
Asthma is a common childhood disease, and the most common cause of medication and hospitalizations of children. The disease is complex and heterogeneous with multiple causes. The aim of the PhD thesis was to investigate the perinatal programming of childhood asthma based on data from clinical birth cohorts focused on childhood asthma, with replication in the Danish national registries when possible. All studies in the thesis are based on either a combination of COPSAC birth cohort data and National registry data, or entirely on registry. The Danish population is well registered in our multiple national registries. For the pediatric population of approximately 2 million children there are no alternatives to public hospitals, which means there is complete nationwide coverage. COPSAC2000 is a clinical birth cohort consisting of 411 infants born to mothers with a history of asthma. The major strength of the clinical cohort data is the close clinical follow-up with physician-diagnosed asthma and related diseases.
The thesis consists of the following papers:
I. Risk of Asthma from Cesarean Delivery Depends on Membrane Rupture. Journal of Pediatrics 2016
II. Preeclampsia Associates with Asthma, Allergy, and Eczema in Childhood. American Journal of Respiratory and Critical Care Medicine 2017
III. Maternal propensity for infections and risk of childhood asthma: a registry-based cohort study. Lancet Respiratory Medicine 2014
IV. Stable admission rate for acute asthma in Danish children since 1977. European Journal of Epidemiology 2016
V. Cesarean section and chronic immune disorders. Pediatrics 2015
Investigates the risk factor cesarean section, where an explorative association in the cohort is further investigated in the registry data where we have power to explore different types of cesarean section, namely sections performed before or after membrane rupture. We find that both types carry a higher risk of offspring asthma compared to vaginally born, but the risk is highest for children born to section before membrane rupture, which could imply microbiome mediated effect on later disease development.
Investigates the maternal pregnancy factor, preeclampsia, which we find to be associated to offspring asthma and particularly allergy in the cohorts. The registry data confirm the findings, and shows a higher risk by longer duration of fetal exposure to preeclampsia.
Is based on an observation from the birth cohort (although in another manuscript) of an association between maternal use of antibiotics during pregnancy and risk of offspring asthma. Reinvestigating this association using the entire Danish population with a new approach to the timing of exposure, we find that the risk factor is unlikely as a causal factor for offspring asthma. Contrary we conclude that maternal use of antibiotics may be seen as a proxy for maternal propensity for infections which appears to be a risk factor for offspring asthma.
Concerns the time trend of childhood asthma. Using the same data source (the Danish National Patient registry) across 35 years we find that the admission rate of school-aged asthma has in fact been stable.
Is based on registry data and concerns the comorbidity of asthma and other chronic inflammatory childhood diseases. We investigate the cesarean section and find several of the diseases to share this common early life risk factor. This suggests early life commonality in the origins of these chronic immune disorders.
Together these studies showcase the advantage of using vastly different data sources especially for an outcome as childhood asthma where the clinical cohort have much stronger phenotyping but lack the power compared to registries where outcome uncertainty is leveraged by a large sample size. Overall the studies conclude several perinatal risk factors for childhood asthma, however some risk factors may be interpreted as proxies for maternal factors.